This Program Project will explore the neurochemistry, electrophysiology, and anatomy of the basal ganglia after damage to the dopamine (DA) containing neurons of the nigrostriatal bundle (NSB). The neurotoxin 6-hydroxydopamine will be administered intracerebrally to adult rats to produce an animal model of Parkinson's disease. Among the issues to be examined are the neurobiological basis of the extensive pre-clinical phase of this disorder and of the impact of stress on parkinsonian symptoms. Possible modes of therapy in the treatment of the disease also will be studied. As part of this endeavor, a multi-disciplinary characterization of many aspects of the normal basal ganglia will be required. Included in this characterization will be an examination of the interactions among dopaminergic, cholinergic, glutamatergic, and GABAergic neurons and an in-depth study of the molecular biology of the catecholamine-synthesizing enzyme, tyrosine hydroxylase (TH). It is expected that these studies will provide insights into the relation between neuropathology and symptomatology in a variety of neurodegenerative disorders, be of value in developing new modes of therapy for these conditions, and add important new information concerning the neurobiology of the basal ganglia.